Transcriptional Programs Uncovering the Genetic Causes of Psychiatric Disorders
Brain development is a complex choreography of cell proliferation, specification, growth, migration and network formation. Distinct genes are expressed during early excitatory corticoneurogenesis in vitro and in the human fetal cortex. Coordinated programs of gene expression drive brain development. Variants of these genetic expression platforms contribute to a wide spectrum of disorders and cognitive function.
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Schizophrenia (SZ) is a highly heritable, psychiatric disorder, with genetic variations ranging from common polymorphisms (SNPs) to rare mutations contributing to disease risk. Genome wide association studies (GWAS) was able to identify SZ gene sets in a modest proportion of a common variant association signal. 50% of genetic SNP-based heritability is captured by loss-of-function intolerant (LoFi) genes. Rare variation in LoFi genes, including many of those implicated in other psychiatric disorders, also contributes to SZ. DLG2, also known as postsynaptic density protein-in (PSD-93) or chapsyn-110, plays a critical role in the molecular organization of multi-protein complexes at the excitatory synapse. In the mature neurons DLG2 is required for normal formation of NMDA receptor signaling complexes. It is abundantly expressed throughout rodent adult brain, including the cortex, hippocampus, striatum, and cerebellum.
Sanders et al., from Cardiff University, University of Sheffield and other premiere institutes in the UK explored the role of DLG2 in neurodevelopment using hESCs (human embryonic stem cells) with DLG-/- loss of function mutation using the CRSIPR-CAS9 system. The team of scientists also investigated the relationship between developmental and mature neuronal pathways in SZ.
Based on the research findings, the team of scientists propose that each variant gene set form a transcriptional cascade regulating neuronal growth, migration, differentiation and network formation. Computational analyses of gene/mRNA regulatory interactions implicate known neurodevelopmental disorder risk genes (CHD8, TCF4, FMRP, BCL11B and TBR1) as regulators of this cascade and reveal pathways through which they may contribute to the disease. A noteworthy observation was down-regulation of neurogenic programs in DLG-/- lines leads to impaired migration, immature action potential generation and delayed expression of cell-type identity of other relevant proteins. It was further confirmed that genetic risk for all disorders was concentrated in LoFi genes, indicating wider relevance for these genes in psychiatric disorders. The study revealed that DLG2 expression is important for cortical excitatory neurodevelopment, but the mechanism by which it operates remains to be determined. Based on its function and the involvement of invertebrate DLG in the developmental Scrib signaling module, DLG may link cell-surface receptors to signal transduction pathways regulating the activation of neurogenic programs.
Although much remains to be uncovered, the study findings sketch the foundations for an integrated etiological model of psychiatric genetic disorders and their developmental origins.
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